Process for the preparation of n-arylmorpholinones

ABSTRACT

Process for the preparation of compounds of the formula (I) in which X has the meaning indicated in Patent Claim  1 , and precursors thereof.

THIS APPLICATION IS A DIVISIONAL OF U.S. SER. No. 11/567,846, FILED 10Feb. 2006.

The invention relates to a process for the preparation of compounds ofthe formula I

in whichX denotes

-   R¹ denotes NO₂, CN, COOR³, CON(R³)₂, COR³, SO₂R⁴, SO₂N(R³)₂, CF₃, F    or Cl,-   R² denotes H, Hal, A, OR³, N(R³)₂, NO₂, CN, COOR³, CON(R³)₂, NR³COA,    NR³CON(R³)₂, NR³COOR³, NR³SO₂A, —[C(R⁵)₂]_(n)—Ar, —[C(R⁵)₂]_(n)—Het,    —[C(R⁵)₂]_(n)-cycloalkyl, COR³, SO₂N(R³)₂ or SO₂R⁴,-   R³ denotes H, A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het,-   R⁴ denotes A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het,-   R⁵ denotes H or A′,-   Ar denotes phenyl which is unsubstituted or mono-, di- or    trisubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN, COOR⁵, CON(R⁵)₂,    NR⁵COA, NR⁵SO₂A, COR⁵, SO₂N(R⁵)₂ or S(O)_(n)A,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms which is unsubstituted    or mono- or disubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN, COOR⁵,    CON(R⁵)₂, NR⁵COA, NR⁵SO₂A, COR⁵, SO₂N(R⁵)₂, S(O)_(n)A and/or    carbonyl oxygen (═O),-   A′ denotes unbranched or branched alkyl having 1-6 C atoms,-   A denotes unbranched, branched or cyclic alkyl having 1-12 C atoms,    in which one or two CH₂ groups may be replaced by O or S atoms    and/or by —CH═CH— groups and/or in addition 1-7H atoms may be    replaced by F,-   Hal denotes F, Cl, Br or I,-   n denotes 0, 1 or 2,-   m denotes 0, 1, 2, 3 or 4,    and salts thereof, characterised in that-   a) a compound of the formula II

X—NH₂  II

in whichX has the meaning indicated above,is reacted with 5-chloro-2,3-dihydro-1,4-dioxin

to give a compound of the formula III

in whichX has the meaning indicated above,

-   b) then a compound of the formula III is cyclised to give a compound    of the formula I,    and-   c) the latter is optionally converted into its salt    by converting a base or acid of the formula I into one of its salts.

The invention had the object of finding novel improved processes for thepreparation of precursors of factor Xa inhibitors.

Compared with known processes from the prior art, the process accordingto the invention is shorter and more efficient.

Factor Xa inhibitors can be employed for combating and preventingthromboembolic diseases, such as thrombosis, myocardial infarction,arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosisafter angioplasty and claudicatio intermittens.

Factor Xa is one of the proteases involved in the complex process ofblood coagulation. Factor Xa catalyses the conversion of prothrombininto thrombin. Thrombin cleaves fibrinogen into fibrin monomers, which,after crosslinking, make an elementary contribution to thrombusformation. Activation of thrombin may result in the occurrence ofthromboembolic diseases. However, inhibition of thrombin may inhibit thefibrin formation involved in thrombus formation.

The inhibition of thrombin can be measured, for example by the method ofG. F. Cousins et al. in Circulation 1996, 94, 1705-1712.

Inhibition of factor Xa can thus prevent the formation of thrombin.

The inhibition of factor Xa and the measurement of the anticoagulant andantithrombotic activity can be determined by conventional in-vitro orin-vivo methods. A suitable method is described, for example, by J.Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223.

The inhibition of factor Xa can be measured, for example by the methodof T. Nara et al. in Thromb. Haemostas. 1994, 71, 314-319.

Coagulation factor VIIa initiates the extrinsic part of the coagulationcascade after binding to tissue factor and contributes to the activationof factor X to give factor Xa. Inhibition of factor VIIa thus preventsthe formation of factor Xa and thus subsequent thrombin formation.

The inhibition of factor VIIa and the measurement of the anticoagulantand antithrombotic activity can be determined by conventional in-vitroor in-vivo methods. A conventional method for the measurement of theinhibition of factor VIIa is described, for example, by H. F. Ronning etal. in Thrombosis Research 1996, 84, 73-81.

Coagulation factor IXa is generated in the intrinsic coagulation cascadeand is likewise involved in the activation of factor X to give factorXa. Inhibition of factor IXa can therefore prevent the formation offactor Xa in a different way.

The inhibition of factor IXa and the measurement of the anticoagulantand antithrombotic activity can be determined by conventional in-vitroor in-vivo methods. A suitable method is described, for example, by J.Chang et al. in Journal of Biological Chemistry 1998, 273, 12089-12094.

A correlation between tissue factor TF/factor VIIa and the developmentof various types of cancer has been indicated by T. Taniguchi and N. R.Lemoine in Biomed. Health Res. (2000), 41 (Molecular Pathogenesis ofPancreatic Cancer), 57-59. The publications listed below describe anantitumoural action of TF-VII and factor Xa inhibitors for various typesof tumour:

K. M. Donnelly et al. in Thromb. Haemost. 1998; 79: 1041-1047;E. G. Fischer et al. in J. Clin. Invest. 104: 1213-1221 (1999);B. M. Mueller et al. in J. Clin. Invest. 101: 1372-1378 (1998);M. E. Bromberg et al. in Thromb. Haemost. 1999; 82: 88-92.WO 02/057236 describes other processes and morpholinone precursors.

The following methods for the preparation of2-(2-chloroethoxy)acetamides are known in the literature:

This method is described, for example, in U.S. Pat. No. 3,074,939, BE776767 and DE 1922613.

This method is described, for example, in G. May, D. Peteri,Arzneim.-Forsch. (Drug Res.) 23, 718 (1973).

This method is described, for example, in DE 2150075.

However, these methods have disadvantages. Thus, many reaction steps arenecessary or the starting materials are expensive.

M. J. Astle, J. D. Welks, J. Org. Chem. 26, 4325 (1961) disclose thefollowing reaction:

We have found, surprisingly, that arylamines, so long as they have apK_(a) of less than or equal to 3, also react with 2-chlorodioxene togive 2-(2-chloroethoxy)acetamides.

In view of M. J. Astle, J. D. Welks, J. Org. Chem. 26, 4325 (1961), thisis unexpected since amines, such as ammonia, benzylamine,8-amino-quinoline or 4-methoxyaniline, do not react or react verypoorly.

Comparison of pK_(a) values:

Benzylamine 9.5 Ammonia 9.24 8-Aminoquinoline 0.7 (NH2 group) and 4.0(quinoline nitrogen). The basic quinoline nitrogen prevents thereaction. 4-Methoxyaniline 5.4 4-Nitroaniline 1.0 4-Cyanoaniline 1.73-Nitroaniline 2.5 2-Methyl-4-nitroaniline 1.04 Methyl 4-aminobenzoate1.5 4-Aminobenzophenone 2.2 2-Nitroaniline −0.23

In the reaction, it is advantageous to add an acid, for example aBrönsted acid, such as hydrochloric acid, or a Lewis acid, oralternatively to add 2,2-dichlorodioxene, a compound which, as is knownfrom the literature (R. K. Summerbell, H. E. Lunk, J. Am. Chem. Soc. 79,p. 4802, 1957), readily dissociates into hydrogen chloride and2-chlorodioxene. The reaction can be carried out in many solvents, forexample toluene, acetonitrile, dioxane, but also in mass, i.e. withoutsolvent. Typical reaction temperatures are 0 to 150° C., generallyaround 80° C., for example between 70 and 90° C.

The advantage of this process lies in the ready accessibility of2-chlorodioxene or 2,2-dichlorodioxane.

The preparation of 2,3-dichlorodioxane is described, for example, in M.lyoda et al, Heterocycles, 54, p. 833, 2001. The thermal elimination ofhydrogen chloride is described in U.S. Pat. No. 2,756,240. This methodgives 2-chlorodioxene, which is contaminated with a certain proportionof 2,2-dichlorodioxane (typically 5 to 50%).

N. V. Kuznetsov, I. I. Krasavtsev, Soy. Prog. Chem. (Engl. Transl.) 44,p. 77, 1987, describe methods for the preparation of 2-chlorodioxenefrom 2,3-dichlorodioxane using sodium hydroxide.

The cyclisation of chloroethoxyacetamides to give morpholinones hashitherto only been described in two publications, in DE 922613 and L.Fumagalli et al. Pharmazie 30, 78 (1975).

Both cases involve triiodobenzoic acid and triiodophenylalkanoic acidderivatives.

However, this process is only suitable for substrates which arewater-soluble, as in the above documents, in which R always contains afree carboxyl group.

We have found that chloroethoxyacetamides can preferably be cyclised togive morpholinones using weak bases, such as, for example, caesiumcarbonate or potassium carbonate, in a suitable solvent, such as, forexample, acetonitrile.

Above and below, A denotes alkyl, is unbranched (linear) or branched,and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotesmethyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butylor tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-,1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl or trifluoromethyl.

A′ preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms,preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl or trifluoromethyl.

Cycloalkyl has 3-7 C atoms and preferably denotes cyclopropyl,cyclobutyl, cyclopentyl or cylohexyl.

Hal preferably denotes F, Cl or Br, but also I.

R¹ preferably denotes NO₂, CN, COOH, COOR³, COR³ or Cl.R² preferably denotes H, Hal or A.R³ preferably denotes H, A′ or —[C(R⁵)₂]_(n)—Ar.R⁴ preferably denotes A.

Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-proylphenyl, o-, m- or p-isopropylphenyl, o-,m- or p-tert-butyl-phenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or p-aminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methyl-aminocarbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxy-phenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)-phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)-phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl,furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-di-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl,3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-,2-amino-5-chloro- or 2-amino-6-chlorophenyl,2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl,2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-di-chloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar preferably denotes, for example, phenyl which is unsubstituted ormono-, di- or trisubstituted by Hal, A, OR⁵, SO₂A, COOR⁵ or CN. Arparticularly preferably denotes, for example, phenyl which isunsubstituted or mono- or disubstituted by Hal, A, OA, SO₂A, SO₂NH₂,COOR⁵ or CN, such as, for example, phenyl, 2-methylsulfonylphenyl,2-aminosulfonylphenyl, 2-, 3- or 4-chlorophenyl, 4-methylphenyl,4-bromophenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl,4-ethoxyphenyl, 2-methoxyphenyl, 3-cyanophenyl or4-ethoxycarbonylphenyl.

Ar very particularly preferably denotes unsubstituted phenyl.

Het is unsubstituted or mono- or disubstituted by Hal, A, OR⁵, N(R⁵)₂,NO₂, CN, COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵SO₂A, COR⁵, SO₂N(R⁵)₂, S(O)_(n)Aand/or carbonyl oxygen (═O) and denotes, for example, 2- or 3-furyl, 2-or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl,1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or-5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-,5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-,4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl,furthermore preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals may also be partially or fully hydrogenated.Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -4- or-5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or-3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylene-dioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)-phenyl or alternatively3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxo-furanyl.

n preferably denotes 0 or 1.m preferably denotes 0, 1 or 2.

The invention preferably relates to a process according to Claim 1 forthe preparation of compounds of the formula I in which

R¹ denotes NO₂, CN, COOR³, COR³ or Cl,R² denotes H, Hal or A.

Preference is furthermore given to a process according to Claim 1 or 2for the preparation of compounds of the formula I in which

-   R¹ denotes NO₂, CN, COOR³, CON(R³)₂, COR³, SO₂R⁴, SO₂N(R³)₂, CF₃,    F_(or) Cl,-   R² denotes H, Hal or A,-   R³ denotes H, A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het.

Preference is furthermore given to a process according to Claim 1 forthe preparation of compounds of the formula I in which Ar denotesphenyl.

Preference is furthermore given to a process for the preparation ofcompounds of the formula I in which R⁴ denotes A.

Preference is furthermore given to a process for the preparation ofcompounds of the formula I in which

R¹ denotes NO₂, CN, COOR³, CON(R³)₂, COR³, CF₃, F or Cl,R² denotes H, Hal or A′,R³ denotes H, A′ or —[C(R⁵)₂]_(n)—Ar,Ar denotes phenyl,R⁵ denotes H or A′,A′ denotes unbranched or branched alkyl having 1-6 C atoms,Hal denotes F, Cl, Br or I,n denotes 0, 1 or 2.

Very particular preference is given to a process according to Claim 1for the preparation of compounds selected from the group

-   4-(4-nitrophenyl)-3-oxomorpholine,-   4-(3-nitrophenyl)-3-oxomorpholine,-   4-(2-nitrophenyl)-3-oxomorpholine,-   2-methyl-4-(4-nitrophenyl)-3-oxomorpholine,-   4-(4-methoxycarbonylphenyl)-3-oxomorpholine,-   4-(4-benzoylphenyl)-3-oxomorpholine.

Preference is furthermore given to a process according to one or more ofClaims 1-6 for the preparation of compounds of the formula I in whichthe amine of the formula II has a pK_(a) value≦3.

The compounds of the formula I can preferably be obtained by, in a firststep a), reacting compounds of the formula II with5-chloro-2,3-dihydro-1,4-dioxin to give a compound of the formula III.

The reaction is generally carried out in an inert solvent, but can alsobe carried out without solvent in mass.

It is advantageous to add an acid, for example a Brönsted acid, such ashydrochloric acid, or a Lewis acid, or alternatively to add2,2-dichlorodioxene, a compound which, as is known from the literature(R. K. Summerbell, H. E. Lunk, J. Am. Chem. Soc. 79, p. 4802, 1957),readily dissociates into hydrogen chloride and 2-chlorodioxene.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, preferably between one and ten hours, the reactiontemperature is between about 0° and 150°, normally between 20° and 130°,preferably between 60° and 110°, very particularly preferably between70° and 90° C.

Suitable inert solvents are, for example, water; hydrocarbons, such ashexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbontetrachloride, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether (methyl glycol or ethyl glycol), ethylene glycoldimethyl ether (diglyme); ketones, such as acetone or butanone; amides,such as acetamide, dimethylacetamide or dimethylformamide (DMF);nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); carbon disulfide; carboxylic acids, such as formic acid oracetic acid; nitro compounds, such as nitromethane or nitrobenzene;esters, such as ethyl acetate, or mixtures of the said solvents.Particular preference is given to acetonitrile.

In a second step b), compounds of the formula III are cyclised to givethe compounds of the formula I.

The reaction is generally carried out in an inert solvent, preferably inthe presence of an alkali or alkaline earth metal hydroxide, carbonateor bicarbonate. Very particular preference is given to weak bases, suchas caesium carbonate or potassium carbonate.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, preferably between one and twenty hours, thereaction temperature is between about 0° and 150°, normally between 0°and 90°, preferably between 10° and 70°, particularly preferably between20° and 50° C.

Suitable inert solvents are, for example, hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether(methyl glycol or ethyl glycol), ethylene glycol dimethyl ether(diglyme); ketones, such as acetone or butanone; amides, such asacetamide, dimethylacetamide or dimethylformamide (DMF); nitriles, suchas acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbondisulfide; carboxylic acids, such as formic acid or acetic acid; nitrocompounds, such as nitromethane or nitrobenzene; esters, such as ethylacetate, or mixtures of the said solvents, particular preference isgiven to acetonitrile.

Process steps a) and b) can also be carried out as a one-pot reaction.When the amine and 2-chlorodioxene have reacted completely, thetemperature of the solution is lowered and an excess of alkali metalcarbonate (typically 1.5 to 4 equivalents) is added and the reactionmixture is stirred until conversion is complete.

A base of the formula I can be converted into the associatedacid-addition salt using an acid, for example by reaction of equivalentamounts of the base and the acid in an inert solvent, such as ethanol,followed by evaporation. Suitable acids for this reaction are, inparticular, those which give physiologically acceptable salts. Thus, itis possible to use inorganic acids, for example sulfuric acid, nitricacid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as orthophosphoric acid, sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids,laurylsulfuric acid. Salts with physiologically unacceptable acids, forexample picrates, can be used for the isolation and/or purification ofthe compounds of the formula I.

On the other hand, compounds of the formula I can be converted into thecorresponding metal salts, in particular alkali metal or alkaline earthmetal salts, or into the corresponding ammonium salts using bases (forexample sodium hydroxide, potassium hydroxide, sodium carbonate orpotassium carbonate).

It is also possible to use physiologically acceptable organic bases,such as, for example, ethanolamine.

The invention also relates to the intermediate compounds of the formulaIII

in whichX denotes

-   R¹ denotes NO₂ or CN,-   R² denotes H, Hal, A, OR³, N(R³)₂, NO₂, CN, COOR³, CON(R³)₂, NR³COA,    NR³CON(R³)₂, NR³COOR³, NR³SO₂A, —[C(R⁵)₂]_(n)—Ar, —[C(R⁵)₂]_(n)—Het,    —[C(R⁵)₂]_(n)-cycloalkyl, COR³, SO₂N(R³)₂ or SO₂R⁴,-   R³ denotes H, A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het,-   R⁴ denotes A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het,-   R⁵ denotes H or A′,-   Ar denotes phenyl which is unsubstituted or mono-, di- or    trisubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN, COOR⁵, CON(R⁵)₂,-   NR⁵COA, NR⁵SO₂A, COR⁵, SO₂N(R⁵)₂ or S(O)_(n)A,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms which is unsubstituted    or mono- or disubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN, COOR⁵,    CON(R⁵)₂, NR⁵COA, NR⁵SO₂A, COR⁵, SO₂N(R⁵)₂, S(O)_(n)A and/or    carbonyl oxygen (═O),-   A′ denotes unbranched or branched alkyl having 1-6 C atoms,-   A denotes unbranched, branched or cyclic alkyl having 1-12 C atoms,    in which one or two CH₂ groups may be replaced by O or S atoms    and/or by —CH═CH— groups and/or in addition 1-7H atoms may be    replaced by F,-   Hal denotes F, Cl, Br or I,-   n denotes 0, 1 or 2,-   m denotes 0, 1, 2, 3 or 4,    and salts thereof.

The intermediate compounds are important for the preparation of thecompounds of the formula I.

The preferred meanings of the radicals correspond to those as indicatedabove, unless expressly stated otherwise.

The invention also relates to the intermediate compounds in which

R¹ denotes NO₂ or CN,R² denotes H, Hal or A,and salts thereof.

Preference is furthermore given to intermediate compounds in which

R¹ denotes NO₂ or CN,R² denotes H, Hal or A,R³ denotes H, A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het,and salts thereof.

Preference is furthermore given to intermediate compounds in which

Ar denotes phenyl,and salts thereof.

Preference is furthermore given to intermediate compounds in which

R⁴ denotes A,and salts thereof.

Particular preference is given to intermediate compounds in which

R¹ denotes NO₂ or CN,R² denotes H, Hal or A′,R³ denotes H, A′ or —[C(R⁵)₂]_(n)—Ar,Ar denotes phenyl,R⁵ denotes H or A′,A′ denotes unbranched or branched alkyl having 1-6 C atoms,Hal denotes F, Cl, Br or I,n denotes 0, 1 or 2,m denotes 0, 1 or 2,and salts thereof.

Particular preference is given to intermediate compounds in which

R¹ denotes NO₂,R² denotes H, Hal or A′,R³ denotes H, A′ or —[C(R⁵)₂]_(n)—Ar,Ar denotes phenyl,R⁵ denotes H or A′,A′ denotes unbranched or branched alkyl having 1-6 C atoms,Hal denotes F, Cl, Br or I,n denotes 0, 1 or 2,m denotes 0, 1 or 2,and salts thereof.

The invention also relates to a process for the preparation ofintermediate compounds of the formula III

in which

X denotes

-   R¹ denotes NO₂, CN, COOR³, CON(R³)₂, COR³, SO₂R⁴, SO₂N(R³)₂,-   CF₃, F or Cl,-   R² denotes H, Hal, A, OR³, N(R³)₂, NO₂, CN, COOR³, CON(R³)₂, NR³COA,    NR³CON(R³)₂, NR³COOR³, NR³SO₂A, —[C(R⁵)₂]_(n)—Ar, —[C(R⁵)₂]_(n)—Het,    —[C(R⁵)₂]_(n)-cycloalkyl, COR³, SO₂N(R³)₂ or SO₂R⁴,-   R³ denotes H, A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het,-   R⁴ denotes A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het,-   R⁵ denotes H or A′,-   Ar denotes phenyl which is unsubstituted or mono-, di- or    trisubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN, COOR⁵, CON(R⁵)₂,    NR⁵COA, NR⁵SO₂A, COR⁵, SO₂N(R⁵)₂ or S(O)_(n)A,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms which is unsubstituted    or mono- or disubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN, COOR⁵,    CON(R⁵)₂, NR⁵COA, NR⁵SO₂A, COR⁵, SO₂N(R⁵)₂, S(O)_(n)A and/or    carbonyl oxygen (═O),-   A′ denotes unbranched or branched alkyl having 1-6 C atoms,-   A denotes branched, branched or cyclic alkyl having 1-12 C atoms, in    which one or two CH₂ groups may be replaced by O or S atoms and/or    by —CH═CH— groups and/or in addition 1-7H atoms may be replaced by    F,-   Hal denotes F, Cl, Br or I,-   n denotes 0, 1 or 2,-   m denotes 0, 1, 2, 3 or 4,    and salts thereof, characterised in that-   a) a compound of the formula II

X—NH₂  II

in whichX has the meaning indicated above,is reacted with 5-chloro-2,3-dihydro-1,4-dioxinand

the compound of the formula III is optionally converted into its salt.

The conditions of the process, in particular the preferred ones, are thesame as indicated under the process for the preparation of the compoundof the formula I.

The preferred meanings of the radicals correspond to those as indicatedabove, unless expressly stated otherwise.

Preference is given to a process for the preparation of intermediatecompounds of the formula III

in which

-   R¹ denotes NO₂ or CN,-   R² denotes H, Hal, A, OR³, N(R³)₂, NO₂, CN, COOR³, CON(R³)₂, NR³COA,    NR³CON(R³)₂, NR³COOR³, NR³SO₂A, —[C(R⁵)₂]_(n)—Ar, —[C(R⁵)₂]_(n)—Het,    —[C(R⁵)₂]_(n)-cycloalkyl, COR³, SO₂N(R³)₂ or SO₂R⁴,-   R³ denotes H, A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het,-   R⁴ denotes A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het,-   R⁵ denotes H or A′,-   Ar denotes phenyl which is unsubstituted or mono-, di- or    trisubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN, COOR⁵, CON(R⁵)₂,    NR⁵COA, NR⁵SO₂A, COR⁵, SO₂N(R⁵)₂ or S(O)_(n)A,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms which is unsubstituted    or mono- or disubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN, COOR⁵,    CON(R⁵)₂, NR⁵COA, NR⁵SO₂A, COR⁵, SO₂N(R⁵)₂, S(O)_(n)A and/or    carbonyl oxygen (═O),-   A′ denotes unbranched or branched alkyl having 1-6 C atoms,-   A denotes unbranched, branched or cyclic alkyl having 1-12 C atoms,    in which one or two CH₂ groups may be replaced by O or S atoms    and/or by —CH═CH— groups and/or in addition 1-7H atoms may be    replaced by F,-   Hal denotes F, Cl, Br or I,-   n denotes 0, 1 or 2,-   m denotes 0, 1, 2, 3 or 4.

Preference is furthermore given to a process for the preparation ofintermediate compounds of the formula III

in whichR¹ denotes NO₂ or CN,R² denotes H, Hal or A.

Preference is furthermore given to a process for the preparation ofintermediate compounds of the formula III

in whichR¹ denotes NO₂ or CN,R² denotes H, Hal or A,R³ denotes H, A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)-Het.

Preference is furthermore given to a process for the preparation ofintermediate compounds of the formula III

in whichAr denotes phenyl.

Preference is also given to a process for the preparation ofintermediate compounds of the formula III

in whichR⁴ denotes A.

Particular preference is given to a process for the preparation ofintermediate compounds of the formula III

in whichR¹ denotes NO₂ or CN,R² denotes H, Hal or A′,R³ denotes H, A′ or —[C(R⁵)₂]_(n)—Ar,Ar denotes phenyl,R⁵ denotes H or A′,A′ denotes unbranched or branched alkyl having 1-6 C atoms,Hal denotes F, Cl, Br or I,n denotes 0, 1 or 2,m denotes 0, 1 or 2.Above and below, all temperatures are indicated in ° C.Mass spectrometry (MS): EI (electron impact ionisation) M⁺;ESI (electrospray ionisation) (M+H)⁺;FAB (fast atom bombardment) (M+H)⁺

EXAMPLE 1 4-(4-Nitrophenyl)-3-oxomorpholine

The preparation is carried out analogously to the following scheme:

1.1 Without Solvent:

1.53 g of a mixture of 2-chlorodioxene and 2,2-dichlorodioxane (molarratio 1:1) are added to 1.00 g (7.24 mmol) of 4-nitroaniline, and themixture is heated to 80° C. with stirring. A solid brown mass formswithin one hour and becomes liquid again and crystallises within thefollowing 12 hours. The crude product is recrystallised from ethanolwith addition of water, giving 1.80 g of2-(2-chloroethoxy)-N-(4-nitrophenyl)acetamide (“A1”) as yellowishcrystals, m.p. 101-102° C. ¹H-NMR (d⁶-DMSO): δ=3.82 (m; 4H), 4.23 (s;2H), 7.91 (d, J=9 Hz, 2H), 8.23 (d, J=9 Hz, 2H), 10.34 (s, 1H).

1.2 In Acetonitrile:

310 mg of a mixture of 2-chlorodioxene and 2,2-dichlorodioxane (molarratio 1:1) are added to a solution of 276 mg (2.00 mmol) of4-nitroaniline in 2 ml of acetonitrile, and the solution is heated at80° C. with stirring for 18 hours. The reaction mixture is evaporated,and the residue is recrystallised from ethanol/water: 360 mg of “A1” asyellowish crystals.

1.3 1 kg of “A1” is dissolved in 5 litres of acetonitrile at roomtemperature, 835 g of potassium carbonate are added, and the mixture isstirred at this temperature for 18 hours. The mixture is warmed to 50°and worked up analogously to Example 6, giving4-(4-nitrophenyl)-3-oxomorpholine (“A2”), m.p. 150-152°.

EXAMPLE 2 4-(4-Nitro-2-methylphenyl)-3-oxomorpholine

1.05 g of a mixture of 2-chlorodioxene and 2,2-dichlorodioxane (molarratio 1:1) are added to a solution of 1.10 g (7.24 mmol) of2-methyl-4-nitroaniline in 20 ml of THF, and the mixture is heated tothe boil. The solvent is distilled off, and the residue, a brown viscousliquid, is heated at 80° C. for 18 hours. After cooling, the residue isrecrystallised from toluene/tert-butyl methyl ether: 1.50 g of2-(2-chloroethoxy)-N-(2-methyl-4-nitrophenyl)acetamide as yellowishcrystals, m.p. 113-114° C. ¹H-NMR (d⁶-DMSO): δ=2.35 (s; 3H), 3.82 (m;4H), 4.23 (s; 2H), 8.05 (d, J=8 Hz, 1H) 8.09 (dd, J=9 Hz, J=1 Hz, 1H),8.16 (d, J=1 Hz, 1H), 9.33 (s, 1H).

The cyclisation is carried out analogously to 1.3,

giving 4-(4-nitro-2-methylphenyl)-3-oxomorpholine, ESI 237.

EXAMPLE 3 4-(2-Nitrophenyl)-3-oxomorpholine

1.12 g of a mixture of 2-chlorodioxene and 2,2-dichlorodioxane (molarratio 89:11) are added to 1.12 g (8.12 mmol) of 2-nitroaniline, and themixture is heated to 80° C. with stirring. A viscous liquid forms, whichis stirred for 3 hours. On cooling to room temperature, the productcrystallises: 2.1 g of 2-(2-chloroethoxy-N-(2-nitrophenyl)acetamide asyellowish crystals. ¹H-NMR (d⁶-DMSO): δ=3.84 (m; 4H), 4.25 (s; 2H), 7.35(t, J=8 Hz, 1H), 7.77 (t, J=8 Hz, 1H), 8.14 (d, J=8 Hz, 1H), 8.30 (d,J=8 Hz, 1H), 10.74 (s, 1H).

The cyclisation is carried out analogously to 1.3,

giving 4-(2-nitrophenyl)-3-oxomorpholine, ESI 223.

EXAMPLE 4 4-(4-Cyanophenyl)-3-oxomorpholine

A mixture of 959 mg (8.12 mmol) of 4-aminobenzonitrile and 1.12 g of amixture of 2-chlorodioxene and 2,2-dichlorodioxane (molar ratio 89:11)is heated at 80° C. with stirring for 18 hours. On cooling to roomtemperature, the product crystallises: 1.9 g of2-(2-chloroethoxy)-N-(4-cyanophenyl)-acetamide as yellowish crystals¹H-NMR (d⁶-DMSO): δ=3.82 (m; 4H), 4.19 (s; 2H), 7.78 (d, J=8 Hz, 2H),7.85 (d, J=8 Hz, 2H), 10.22 (s, 1H).

The cyclisation is carried out analogously to 1.3,

giving 4-(4-cyanophenyl)-3-oxomorpholine, ESI 203.

EXAMPLE 5 4-(4-Methoxycarbonylphenyl)-3-oxomorpholine

A mixture of 1.23 mg (8.12 mmol) of methyl 4-aminobenzoate and 1.12 g ofa mixture of 2-chlorodioxene and 2,2-dichlorodioxane (molar ratio 89:11)is heated at 80° C. with stirring for 18 hours. On cooling to roomtemperature, the product crystallises: 2.2 g of methyl4-[2-(2-chloroethoxy)acetylamino]benzoate as yellowish crystals. ¹H-NMR(d⁶-DMSO): δ=3.82 (m; 7H), 4.20 (s; 2H), 7.82 (d, J=8 Hz, 2H), 7.93 (d,J=8 Hz, 2H), 10.15 (s, 1H).

The cyclisation is carried out analogously to 1.3,

giving 4-(4-methoxycarbonylphenyl)-3-oxomorpholine, ESI 236.

EXAMPLE 6 One-Pot Reaction for the Preparation of “A2”

6.40 g of 2-chlorodioxene (contains 6% of 2,2-dichlorodioxane) are addedto a solution of 6.00 g (24.9 mmol) of 4-nitroaniline in 40 ml ofacetonitrile, and the mixture is stirred at 80° C. for 18 hours. Thereaction solution is cooled to 40° C., 18.0 g (130 mmol) of potassiumcarbonate are added, and the mixture is stirred at this temperature for14 hours.

The reaction mixture is filtered, the residue is washed well withacetonitrile, and the filtrate is evaporated. The residue isrecrystallised from acetonitrile: 8.2 g of brownish crystals (“A2”),m.p. 150-152° C. ¹H-NMR (d⁶-DMSO): δ=3.86 (t, J=5 Hz; 2H), 4.02 (t, J=5Hz; 2H), 4.28 (s; 2H), 7.77 (d, J=9 Hz, 2H), 8.28 (d, J=9 Hz, 2H).

EXAMPLE 7 4-(3-Nitrophenyl)-3-oxomorpholine

A mixture of 1.12 g (8.12 mmol) of 3-nitroaniline and 1.11 g of2-chlorodioxene (contains 6% of 2,2-dichlorodioxane) is heated at 80° C.with stirring for 24 hours, giving 2.1 g of2-(2-chloroethoxy)-N-(3-nitrophenyl)-acetamide as brownish oil. ESI 259.

The cyclisation is carried out analogously to 1.3,

giving 4-(3-nitrophenyl)-3-oxomorpholine, ESI 223.

EXAMPLE 8 4-(4-Benzoylphenyl)-3-oxomorpholine

A mixture of 1.60 g (8.12 mmol) of 4-aminobenzophenone and 1.11 g of2-chlorodioxene (contains 6% of 2,2-dichlorodioxane) is heated at 80° C.with stirring for 24 hours, giving 2.6 g ofN-(4-benzoylphenyl)-2-(2-chloroethoxy)acetamide as brown oil. ESI 318.

The cyclisation is carried out analogously to 1.3,

giving 4-(4-benzoylphenyl)-3-oxomorpholine, ESI 282.

EXAMPLE 9 4-(3-Fluorophenyl)-3-oxomorpholine

A mixture of 12.0 g (108 mmol) of 3-fluoraniline and 16 g of2-chlorodioxene (contains 6% of 2,2-dichlorodioxane) is heated at 100°C. for 24 hours. The mixture is allowed to cool, and excess2-chlorodioxene is removed under reduced pressure, giving 25 g of2-(2-chloroethoxy)-N-(3-fluorophenyl)acetamide as brown oil; ESI 232.This oil is dissolved in 400 ml of acetonitrile, and 84.7 g (260 mmol)of caesium carbonate are added. The suspension formed is stirred at roomtemperature for 18 hours. The reaction mixture is filtered, and thefiltrate is evaporated, giving 21.0 g of4-(3-fluorophenyl)morpholin-3-one as brown oil; ESI 196. ¹H-NMR(d⁶-DMSO): δ=3.77 (t, J=5 Hz; 2H), 3.97 (t, J=5 Hz; 2H), 4.23 (s; 2H),7.11 (dddd, J₁=8 Hz, J₂=8 Hz, J₃=2 Hz, J₄=0.5 Hz, 1H), 7.26 (ddd, J₁=8Hz, J₂=2 Hz, J₃=0.5 Hz, 1H), 7.34 (ddd, J₁=10 Hz, J₂=2 Hz, J₃=2 Hz, 1H),7.45 (ddd, J₁=8 Hz, J₂=8 Hz, J₃=7 Hz, 1H).

EXAMPLE 10 4-(3-Methyl-4-nitrophenyl)-3-oxomorpholine

12.8 g of 2-chlorodioxene (contains 6% of 2,2-dichlorodioxane) are addedto a solution of 10.0 g (65.7 mmol) of 3-methyl-4-nitroaniline in 250 mlof acetonitrile, and the mixture is stirred at 80° C. for 66 hours. Thereaction solution is cooled to room temperature, 42.8 g (131 mmol) ofcaesium carbonate are added, and the mixture is stirred at roomtemperature for 18 hours. The reaction mixture is filtered, the residueis washed well with acetonitrile, and the filtrate is evaporated. Theresidue is recrystallised from a little acetonitrile, giving 12.8 g(83%) of 4-(3-methyl-4-nitrophenyl)morpholin-3-one as yellowish solid.ESI 236. ¹H-NMR (d⁶-DMSO): δ=2.54 (s; 2H), δ=3.82 (t, J=5 Hz; 2H), 4.00(t, J=5 Hz; 2H), 4.25 (s; 2H), 7.57 (m; 2H), 8.04 (d, J.=8 Hz; 1H).

4-(2-Chloro-5-fluoro-4-nitrophenyl)-3-oxomorpholine is obtainedanalogously

EXAMPLE 11 4-(2-Bromo-5-nitrophenyl)-3-oxomorpholine is obtainedanalogously to Example 7

4-(2-Methoxycarbonyl-5-nitrophenyl)-3-oxomorpholine is obtainedanalogously to Example 7

1.-14. (canceled)
 15. A compound of the formula III in which

X denotes

R¹ denotes NO₂ or CN, R² denotes H, Hal, A, OR³, N(R³)₂, NO₂, CN, COOR³,CON(R³)₂, NR³COA, NR³CON(R³)₂, NR³COOR³, NR³SO₂A, —[C(R⁵)₂]_(n)—Ar,—[C(R⁵)₂]_(n)—Het, —[C(R⁵)₂]_(n)-cycloalkyl, COR^(S), SO₂N(R³)₂ orSO₂R⁴, R³ denotes H, A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het, R⁴denotes A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het, R⁵ denotes H or A′, Ardenotes phenyl which is unsubstituted or mono-, di- or trisubstituted byHal, A, OR⁵, N(R⁵)₂, NO₂, CN, COOR^(S), CON(R⁵)₂, NR⁵COA, NR⁵SO₂A,COR^(S), SO₂N(R⁵)₂ or S(O)_(n)A, Het denotes a mono- or bicyclicsaturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/orS atoms which is unsubstituted or mono- or disubstituted by Hal, A, OR⁵,N(R⁵)₂, NO₂, CN, COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵SO₂A, COR^(S), SO₂N(R⁵)₂,S(O)_(n)A and/or carbonyl oxygen (═O), A′ denotes unbranched or branchedalkyl having 1-6 C atoms, A denotes unbranched, branched or cyclic alkylhaving 1-12 C atoms, in which one or two CH₂ groups may be replaced by Oor S atoms and/or by —CH═CH— groups and/or in addition 1-7H atoms may bereplaced by F, Hal denotes F, Cl, Br or I, n denotes 0, 1 or 2, mdenotes 0, 1, 2, 3 or 4, or a salt thereof.
 16. A compound according toclaim 15 in which R¹ denotes NO₂ or CN, R² denotes H, Hal or A, or asalt thereof.
 17. A compound according to claim 15, in which R¹ denotesNO₂ or CN, R² denotes H, Hal or A, R³ denotes H, A, —[C(R⁵)₂]_(n)—Ar or—[C(R⁵)₂]_(n)—Het, or a salt thereof.
 18. A compound according to claim15 in which Ar denotes phenyl, or a salt thereof.
 19. A compoundaccording to claim 15 in which R⁴ denotes A, or a salt thereof.
 20. Acompound according to claim 15 in which R¹ denotes NO₂ or CN, R² denotesH, Hal or A′, R³ denotes H, A′ or —[C(R⁵)₂]_(n)—Ar, Ar denotes phenyl,R⁵ denotes H or A′, A′ denotes unbranched or branched alkyl having 1-6 Catoms, Hal denotes F, Cl, Br or I, n denotes 0, 1 or 2, m denotes 0, 1or 2, or a salt thereof.
 21. A compound according to claim 20 in whichR¹ denotes NO₂, R² denotes H, Hal or A′, R³ denotes H, A′ or—[C(R⁵)₂]_(n)—Ar, Ar denotes phenyl, R⁵ denotes H or A′, A′ denotesunbranched or branched alkyl having 1-6 C atoms, Hal denotes F, Cl, Bror I, n denotes 0, 1 or 2, m denotes 0, 1 or 2, or a salt thereof.
 22. Aprocess for the preparation of a compound of the formula III

in which X denotes

R¹ denotes NO₂, CN, COOR³, CON(R³)₂, COR³, SO₂R⁴, SO₂N(R³)₂, CF₃, F orCl, R² denotes H, Hal, A, OR³, N(R³)₂, NO₂, CN, COOR³, CON(R³)₂, NR³COA,NR³CON(R³)₂, NR³COOR³, NR³SO₂A, —[C(R⁵)₂]_(n)—Ar, —[C(R⁵)₂]_(n)—Het,—[C(R⁵)₂]_(n)-cycloalkyl, COR³, SO₂N(R³)₂ or SO₂R⁴, R³ denotes H, A,—[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het, R⁴ denotes A, —[C(R⁵)₂]_(n)—Ar or—[C(R⁵)₂]_(n)—Het, R⁵ denotes H or A′, Ar denotes phenyl which isunsubstituted or mono-, di- or trisubstituted by Hal, A, OR^(S), N(R⁵)₂,NO₂, CN, COOR^(S), CON(R⁵)₂, NR⁵COA, NR⁵SO₂A, COR^(S), SO₂N(R⁵)₂ orS(O)_(n)A, Het denotes a mono- or bicyclic saturated, unsaturated oraromatic heterocycle having 1 to 4 N, O and/or S atoms which isunsubstituted or mono- or disubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN,COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵SO₂A, COR^(S), SO₂N(R⁵)₂, S(O)_(n)A and/orcarbonyl oxygen (═O), A′ denotes unbranched or branched alkyl having 1-6C atoms, A denotes unbranched, branched or cyclic alkyl having 1-12 Catoms, in which one or two CH₂ groups may be replaced by O or S atomsand/or by —CH═CH— groups and/or in addition 1-7H atoms may be replacedby F, Hal denotes F, Cl, Br or I, n denotes 0, 1 or 2, m denotes 0, 1,2, 3 or 4, and salts thereof, characterised in that a) a compound of theformula IIX—NH₂  II in which X has the meaning indicated above, is reacted with5-chloro-2,3-dihydro-1,4-dioxin

and the compound of the formula III is optionally converted into itssalt.
 23. A process according to claim 22 for the preparation of acompound of the formula III in which R¹ denotes NO₂ or CN, R² denotes H,Hal, A, OR³, N(R³)₂, NO₂, CN, COOR^(S), CON(R³)₂, NR³COA, NR³CON(R³)₂,NR³COOR³, NR³SO₂A, —[C(R⁵)₂]_(n)—Ar, —[C(R⁵)₂]_(n)—Het,—[C(R⁵)₂]_(n)-cycloalkyl, COR^(S), SO₂N(R³)₂ or SO₂R⁴, R³ denotes H, A,—[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het, R⁴ denotes A, —[C(R⁵)₂]_(n)—Ar or—[C(R⁵)₂]_(n)—Het, R⁵ denotes H or A′, Ar denotes phenyl which isunsubstituted or mono-, di- or trisubstituted by Hal, A, OR⁵, N(R⁵)₂,NO₂, CN, COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵SO₂A, COR⁵, SO₂N(R⁵)₂ or S(O)_(n)A,Het denotes a mono- or bicyclic saturated, unsaturated or aromaticheterocycle having 1 to 4 N, O and/or S atoms which is unsubstituted ormono- or disubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN, COOR⁵, CON(R⁵)₂,NR⁵COA, NR⁵SO₂A, COR⁵, SO₂N(R⁵)₂, S(O)_(n)A and/or carbonyl oxygen (═O),A′ denotes unbranched or branched alkyl having 1-6 C atoms, A denotesunbranched, branched or cyclic alkyl having 1-12 C atoms, in which oneor two CH₂ groups may be replaced by O or S atoms and/or by —CH═CH—groups and/or in addition 1-7H atoms may be replaced by F, Hal denotesF, Cl, Br or I, n denotes 0, 1 or 2, m denotes 0, 1, 2, 3 or
 4. 24. Aprocess according to claim 23 for the preparation of a compound of theformula III in which R¹ denotes NO₂ or CN, R² denotes H, Hal or A.
 25. Aprocess according to claim 23 for the preparation of a compound of theformula III in which R¹ denotes NO₂ or CN, R² denotes H, Hal or A, R³denotes H, A, —[C(R⁵)₂]_(n)—Ar or —[C(R⁵)₂]_(n)—Het.
 26. A processaccording to claim 23 for the preparation of a compound of the formulaIII in which Ar denotes phenyl.
 27. A process according to claim 23 forthe preparation of a compound of the formula III in which R⁴ denotes A.28. A process according to claim 23 for the preparation of a compound ofthe formula III in which R¹ denotes NO₂ or CN, R² denotes H, Hal or A′,R³ denotes H, A′ or —[C(R⁵)₂]_(n)—Ar, Ar denotes phenyl, R⁵ denotes H orA′, A′ denotes unbranched or branched alkyl having 1-6 C atoms, Haldenotes F, Cl, Br or I, n denotes 0, 1 or 2, m denotes 0, 1 or 2.